靶向氧化还原代谢和低剂量放疗协同激活 cGAS-STING 通路以提高 NK 细胞治疗肝细胞癌的疗效

Adoptive natural killer (NK) cell therapy (ANKCT) is a promising strategy for hepatocellular carcinoma (HCC); however, its efficacy is hampered by insufficient NK cell homing and the immunosuppressive activity of M2-polarized tumor-associated macrophages (TAMs). Activation of the cyclic guanosine monophosphate (GMP)-adenosine monophosphate synthase (AMP) synthase-stimulator of interferon genes (cGAS-STING) pathway enhances NK-cell recruitment and reprograms TAMs toward a proinflammatory M1 phenotype.

Radiation therapy (RT) activates the cGAS-STING pathway by inducing reactive oxygen species (ROS)-mediated DNA damage. Compared with high-dose irradiation, low-dose radiotherapy (LDRT) offers advantages, including reduced toxicity and enhanced antitumor immunity.

However, the robust thioredoxin (Trx) and glutathione (GSH) antioxidant systems in HCC inhibit LDRT-induced ROS accumulation, thereby limiting immune activation. These limitations highlight the need for auxiliary strategies to complement LDRT-induced immunogenicity.

Here, we developed a biomimetic nanoparticle in which auranofin-loaded MOF-199 is cloaked with tumor cell membranes (A@MMOF). A@MMOF disrupts tumor redox homeostasis by irreversibly inhibiting the GSH and Trx antioxidant systems while inducing GSH-dependent Cu release from the MOF framework.

The subsequent reduction of Cu to Cu catalyzes Fenton-like reactions, markedly amplifying the intracellular ROS levels. By providing a sustained redox-driven stimulus, A@MMOF compensates for the insufficient oxidative stress induced by LDRT, leading to robust activation of the cGAS-STING pathway.

Thus, A@MMOF synergizes with LDRT to remodel the tumor microenvironment, enhance NK cell infiltration and activation, and ultimately improve the efficacy of ANKCT in HCC.